DESCRIPTION: (Applicant's abstract) A recently discovered mechanism of inflammatory injury, the "poly (ADP-ribose) synthetase (PARS) pathway," has been implicated in the pathogenesis of various forms of neuronal injury. Triggered by oxidant-induced DNA single strand breaks, PARS catalyzes an energy-consuming polymerization of ADP-ribose, resulting in NAD depletion, inhibition of glycolysis and mitochondrial respiration, and the ultimate reduction of intracellular high energy phosphates. The applicants have developed a novel class of compounds with neuroprotective potential. In this proposal, we present evidence that INH2BP, a potent non-toxic PARS inhibitor, reduces oxidant-induced cellular injury. Furthermore, we present evidence for the role of PARS in a murine model of stroke. Inotek's long-term intention to develop INH2BP as a drug for the treatment of neuroinjury. The specific aim of the present proposal is to perform definitive in vivo studies in murine model of Parkinson's disease in order to test whether INH2BP can be developed for the experimental therapy of this condition. The results of the present application will permit application for the Phase 2 SBIR funding to support: pre-clinical pharmaceutical testing (advanced toxicity determinations, pathology, stability, pharmacokinetics, in vivo efficacy), investigational drug application to the FDA, and Phase 1 clinical trial. PROPOSED COMMERCIAL APPLICATION: Novel drugs for the therapy of Parkinson's Disease.